This Article Abstract Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Cardoso, J. F. Articles by Costa, A. M. A. Search for Related Content PubMed PubMed Citation Articles by Cardoso, J. F. Articles by Costa, A. M. A. Social Bookmarking                         What's this?

Effects of Cigarette Smoke in Mice Wound Healing is Strain Dependent

Histology and Embryology Department, State University of Rio de Janeiro, Rio de Janeiro, Brazil

Correspondence: Address correspondence to Dr. Andréa Monte Alto Costa, State University of Rio de Janeiro (UERJ), Histology and Embryology Department, Rua Professor Manuel de Abreu, 444, 3° andar, 20550-170, Rio de Janeiro, RJ, Brazil; e-mail:amacosta{at}uerj.br

	Abstract

Top Abstract Introduction Material and Methods Results Discussion References

 
It has been clinically and experimentally shown that cigarette smokers suffer from impaired wound healing, but the mechanisms that lead to the alterations are not well understood. The aim of this study was to investigate if the effects of cigarette smoke exposure on excisional cutaneous wound healing are different depending on the strain (Swiss, BALB/c and C57BL/6 mice) studied. Male mice were exposed to smoke of nine whole cigarettes per day, 3 times/day, daily, for 10 days. In the 11th day a full-thickness excisional wound was performed. Control group was sham-exposed and also had a full-thickness excisional wound. The cigarette smoke exposure protocol was performed until euthanasia. Animals were euthanatized 14 days after wounding. Wound contraction was evaluated 7 and 14 days after lesion. Sections were stained with hematoxylin-eosin, Sirius red or toluidine blue and immunostained for alpha-smooth muscle actin. Smoke exposed animals presented delay in wound contraction, in fibroblastic and inflammatory cells recruitment and in myofibroblastic differentiation; those alterations were strain dependent. Cigarette smoke exposure also affected mast cells recruitment and neoepidermis thickness. In conclusion, the present study demonstrated that the effects of cigarette smoke in mice cutaneous wound healing are related to mice strain studied.

Key Words: Cigarette smoke • wound healing • myofibroblasts • mast cells • connective tissue

	Introduction

Top Abstract Introduction Material and Methods Results Discussion References

 
Cutaneous wound healing is a complex and dynamic process that involves many coordinated events including inflammation, cell migration, cell proliferation, angiogenesis, matrix deposition, and remodeling (Singer and Clark, 1999). These events are managed by a number of different cell types such as keratinocytes, fibroblasts, and inflammatory and endothelial cells (Martin, 1997) which are influenced by many factors. The relationship between smoking and its detrimental effects on wound healing were first reported by Mosely and Finseth (Mosely and Finseth, 1977) that observed impaired healing of a wound hand in a smoker with arteriosclerosis. After this study, epidemiological and experimental studies have pointed to a significant correlation between cigarette smoke and alterations in the process of tissue remodeling, such as delayed and abnormal wound healing (Frick and Seals, 1994; Manassa et al., 2003; Silverstein, 1992).

Cigarette smoke is a complex mixture of chemicals containing more than 4,000 different constituents, but those of greatest interest are nicotine, carbon monoxide and hydrogen cyanide (Silverstein, 1992). Knowledge of the cutaneous effects of smoking is important because it provides another tool for counseling patients on the dangers of smoking and provides them an effective motivation to quite smoking, especially those who may be more concerned about their outward appearance than about the potential internal damage associated with smoking (Smith and Fenske, 1996).

Most published reports were based on retrospective clinical analyses; few prospective controlled studies have been conducted investigating the actions of cigarette smoke on wound healing (Reus et al., 1992; Manassa; Hertl and Olbrisch, 2003). In animal models, studies are mainly focused in investigate which phases of wound healing are compromised by cigarette smoke (Lawrence et al., 1984; Craig and Rees, 1985).

A large variety of mice strains are used in experimental studies. Different strains present a large range of sensitivity to behavioral effects of nicotine (the major constituent of the particulate phase of tobacco smoke) (Collins and Marks, 1991) and physiological effects of cigarette smoke exposure (Bartalesi et al., 2005; Guerassimov et al., 2004). The choice of a good experimental model to study cigarette smoke effects on cutaneous excisional wound healing is an important tool to understand the cigarette smoke pathophysiological mechanisms at the cellular and molecular level. The purpose of this study was to investigate the effects of cigarette smoke exposure on wound healing in three mice strains (Swiss, BALB/c and C57BL/6) and point out the differences among the strains.

	Material and Methods

Top Abstract Introduction Material and Methods Results Discussion References

 
Animals
All animal procedures are in accordance with the Guide for Use and Care of Animals and were approved by the Ethical Committee for Animal Use of State University of Rio de Janeiro.

Male mice (10 weeks of age) of three different strains: Swiss, BALB/c and C57BL/6 were used. Animals were housed under controlled environmental conditions (light/dark cycle, temperature and humidity) and had free access to food and water during the experiment.

Cigarette smoke exposure and wounding
In each strain, animals were separated in control (n = 15) and smoke exposed groups (n = 21). Smoke exposed groups had the hole-body exposed, in an inhalation chamber, to a smoke-air mixture of commercial filtered Virginia cigarette, 3 times/day, 7 days/week, during the entire experiment, as already described (Valenca et al., 2004). The cigarette smoke exposure protocol started 10 days before the excisional wound and continued until the end of the experiment. The control group was sham-exposed.

On day 0 (10 days after the beginning of smoke or sham exposition), the animals were anaesthetized with ketamine (5 mg/kg, ip) and xylazine (2 mg/kg, ip). The dorsal surface was shaved and a full-thickness excisional wound (1 cm²) was performed. The wound was not sutured or covered and healed by second intension.

Macroscopic analysis
To evaluate wound contraction, a transparent plastic sheet was placed over the wound and the wound margins were traced. After digitalization, the wound area was evaluated using Zeiss image-processing system KS400 (Zeiss-Vision; Oberkochen, Germany) (Souza et al., 2005). Wound area was measured soon after wounding and 7 and 14 days later. Data are expressed as a percentage of the initial wound area.

Tissue harvesting and staining
Mice were sacrificed 14 days after wounding in a CO₂ chamber. Fragments of wound with adjacent normal skin tissue were formalin-fixed (pH 7.2) and paraffin-embedded.

Sections (5 µm) were stained with hematoxylin-eosin, for general evaluation of wound and normal skin, epidermis and neoepidermis thickness and inflammatory infiltrate, with Sirius red for analysis of collagen fibers arrangement and with toluidine blue for analysis and quantification of mast cells.

Inflammatory and Mast Cells Quantification
The amount of inflammatory cells was evaluated in hematoxylin-eosin stained sections. Ten random fields (0.119 mm²) were counted using the x40 objective (Olympus BH-2, Olympus Optical Co. Ltd; Tokyo, Japan) in middle region of granulation tissue. The amount of mast cells was evaluated in toluidine blue stained sections. Six random fields (0.119 mm²), located in the superficial region of granulation tissue, were counted using the same objective and microscope. The percentage of degranulating mast cells was also evaluated. Results are expressed as mean of cells per field. All analyses were repeated without significant difference among them.

Epidermal and neoepidermal thickness
Epidermis and neoepidermis thickness were evaluated in hematoxylin-eosin stained sections using Zeiss image-processing system KS400 (Zeiss-Vision; Oberkochen, Germany). Epidermis and neoepidermis thickness was measured from dermo-epidermal junction to the outermost extent of the granular layer. Three random fields were analyzed using the x40 objective, with three measures in each field (Olympus BH-2). Data are expressed as the mean of measurements in each wound.

Immunohistochemistry
Myofibroblasts expressing alpha-smooth muscle actin were localized by immunohistochemistry. To allow the use of a mice monoclonal antibody in mouse tissue, some modifications in standard technique were performed. Sections (5 µm) were deparaffinized, hydrated and after washing in PBS (phosphate buffered saline) sections were incubated with EnVision system (DAKO; Carpinteria, CA) for 50 minutes to allow anti-mouse IgG to bind to tissue, then peroxidase (endogenous and polymer-linked) was inhibited by incubation in 3% H₂O₂ in methanol, for 30 minutes. After washing, sections were incubated with a solution of a monoclonal antibody against alpha-smooth muscle actin (DAKO) (1:200) and Envision (1:20) in PBS/BSA (PBS/bovine serum albumin) 1% overnight. Diaminobenzidine was used as chromogen. Sections were counterstained with Delafield’s hematoxylin. Negative controls were performed replacing primary antibody by PBS/BSA and no labeling was observed.

Statistical Analysis
All data are presented as mean ± standard error of mean (SEM). Data concerning lesion area, inflammatory and mast cells amount, epidermis and neoepidermis thickness were analyzed with non-parametric Mann-Whitney test. Statistical analysis was done using the software Graph Pad Instat version 3.01 (GraphPad Software Inc.; CA, USA).

	Results

Top Abstract Introduction Material and Methods Results Discussion References

 
Macroscopic Analysis
In Swiss mice, smoke exposure did not altered wound contraction 7 or 14 days after wounding. In BALB/c mice smoke exposure delayed wound contraction 7 and 14 days after wounding (p < 0.01 and p < 0.05, respectively). In the same way, smoke exposure delayed wound contraction in C57BL/6 mice 7 and 14 days after wounding (p < 0.01 and p < 0.001, respectively). (Figure 1).

View larger version (30K): [in this window] [in a new window]   Figure 1 Wound contraction evaluation in Swiss, BALB/c and C57BL/6 mice strains (mean ± SEM).

General Histology
In Swiss control group, 14 days after wounding, numerous inflammatory (2.52 ± 0.3 cells/field) and fibroblastic cells were observed in granulation tissue; in the smoke exposed group the amount of inflammatory (1.73 ± 0.2 cells/field; p < 0.05) and fibroblastic cells was reduced. In BALB/c control group, 14 days after wounding, a reduced amount of inflammatory (1.68 ± 0.3 cells/field) and fibroblastic cells were observed compared to smoke exposed group in granulation tissue (2.45 ± 0.3 inflammatory cells/field; p < 0.05). C57BL/6 control and smoke exposed groups presented the same pattern of inflammatory and fibroblastic cells distribution observed in counterpart of BALB/c animals (control: 1.1 ± 0.2 inflammatory cells/field, exposed 1.8 ± 0.2 inflammatory cells/field; p < 0.05) (Figure 2).

View larger version (622K): [in this window] [in a new window]   Figure 2 Granulation tissue on wound area of different mice strains 14 days after wounding. Swiss control group (a) presented a higher amount of inflammatory and fibroblast-like cells than smoke exposed group (b). BALB/c control group (c) presented a lower amount of inflammatory and fibroblast-like cells than smoke exposed group (d). C57BL/6 control group (e) presented a lower amount of inflammatory and fibroblast-like cells than smoke exposed group (f). Hematoxylin-Eosin. Bar 30 µm.

Data concerning mast cell quantification are presented in Figure 3. In Swiss animals, smoke exposed group presented higher amount of mast cells (+117%) than control group (p < 0.001). BALB/c smoke exposed group showed a lower amount of mast cells (–78%) than control group (p < 0.0001). On the other hand, C57BL/6 smoke exposed group also presented higher amount of mast cells (+214%) compared to control group (p < 0.05).

View larger version (29K): [in this window] [in a new window]   Figure 3 Mast cells/field in wound area of control and smoke exposed groups. (mean ± SEM).

Cigarette smoke exposure did not affect mast cell degranulation in any strain. Among strains no differences were observed in the amount of degranulating mast cells.

Epidermis and neoepidermis thickness
Epidermal thickness was not altered by cigarette smoke exposure in Swiss strain. In BALB/c smoke exposed animals epidermis was thinner (9.1 ± 2.7 mm) than control animals (p < 0.05). In C57BL/6 smoke exposed animals epidermis was thicker than in control animals (p = 0.01). (Figure 4a).

View larger version (33K): [in this window] [in a new window]   Figure 4 Epidermis (a) and neo-epidermis (b) thickness in control and smoke exposed groups (mean ± SEM).

Organization and distribution of collagen fibers
Collagen organization was evaluated in tissue sections stained with Sirius red observed under polarization. In normal skin collagen fibers were yellow-red, thick and presented a basket-like pattern in all experimental groups. Fourteen days after wounding, collagen fibers, in superficial region of scar, were mainly greenish, some yellow-greenish and yellow-red fragmented collagen fibers were always present. Collagen fibers were loosely arranged and parallel to surface. In deep region of scar collagen fibers were arranged in bundles (data not shown). There were no significant differences in collagen arrangement in all animal groups (control or exposed), neither among strains.

Analysis of myofibroblasts
Myofibroblasts were fusiform, parallel to surface and homogeously distributed in granulation tissue of all strains and experimental groups. Fourteen days after wounding, the density of myofibroblasts in smoke exposed groups was higher than in control group of all strains (Figure 5).

View larger version (711K): [in this window] [in a new window]   Figure 5 Myofibroblast distribution on wound area of different mice strains 14 days after wounding. Swiss control group (a) presented a lower amount of myofibroblasts than smoke exposed group (b). BALB/c control group (c) presented a lower amount of myofibroblasts than smoke exposed group (d). C57BL/6 control group (e) presented a lower amount of myofibroblasts than smoke exposed group (f). Immunohistochemistry against alpha-smooth muscle actin. Bar 30 µm.

	Discussion

Top Abstract Introduction Material and Methods Results Discussion References

The detrimental effects of smoking on wound healing were first related by researches who observed impaired healing of a hand wound in a smoker with arteriosclerosis (Mosely and Finseth, 1977). From this observation many clinic studies were developed, but the use of animal models are still an important tool to investigate the effects of cigarette smoke exposure on wound healing. However, it is very important the definition of what experimental model is more appropriate. Studies, mainly involving behavioral aspects, showed that different strains respond in different ways to nicotine (Garg, 1969; Marks et al., 1983b), this fact has stimulated many studies about genotype influence on sensitivity to nicotine, the main component of cigarette smoke (Hatchell and Collins, 1977; Mohammed, 2000). For example Marks et al. (1983) studied four strains (BALB/c, C57BL/6, DBA/2 and C3H/2) to observe behavioral and physiological effects of nicotine and showed that C57BL/6 and DBA/2 strains were more sensitive to nicotine depressive effects while C3H/2 strain showed more sensitivity to nicotine stimulant effects. However, BALB/c strain showed more diverse effects, being sometimes more and others less sensitive to nicotine effects, evidencing nicotine effects in this strain are not regulated by an unique mechanism; the authors also suggested that nicotine metabolism is not important in controlling genotype-dependent differences in sensitivity to the drug (Marks et al., 1983a).

Swiss strain seems to be more resistant to nicotine behavioral depressive effects requiring a higher dose to present the same depressive effects presented by others strains (Tizabi et al., 1998). We can speculate that the absence of effects in wound contraction in Swiss smoke exposed mice may be due to a resistance to nicotine. This resistance to nicotine is probably due to genetic background since studies published still had not succeed to demonstrate alterations on nicotine metabolism in different strains (Marks; Burch and Collins, 1983b).

Cigarette smoke have been associated with increase of the neutrophils infiltrate (Chow et al., 1997) as well as with alterations in its functions (chemotaxis and phagocytosis) (Kenney et al., 1977; Seymour, 1991; Lannan et al., 1992). The possible mechanism by which occurs the increase of neutrophils amount would be the stimulation of interleukin 8 (IL-8) release, which is powerful chemotactic factor to leukocytes and is produced by many types of cells such as monocytes, keratinocytes, lymphocytes, eosinophils, fibroblasts and endothelial cells (Wang et al., 2000). It is known that IL-8 first exerts its effect in neutrophils (Hebert and Baker, 1993; Graves and Jiang, 1995) and that the cigarette smoke can induce the release of IL-8 in cells of the bronchial epithelia (Mio et al., 1997) as well as in endothelial cells (Wang; Ye; Zhu and Cho, 2000). These effects of the cigarette smoke on neutrophils may explain the higher amount of inflammatory cells found in granulation tissue of C57BL/6 and BALB/c mice strains exposed to cigarette smoke. And the prolongation of inflammatory phase explains the delay in wound healing process.

Our study showed an alteration in mast cells recruitment according to the strain studied. It is known that mast cells have an important role in the inflammatory phase of wound healing, mainly by neutrophils recruitment through the release of chemotactic factors (Abraham and Malaviya, 1997; Schwartz and Austen, 1984) but it was also shown that the excess of mast cells mediators (such as chymase) may impair epithelial cell migration (Ebihara et al., 2005). A previous study showed that cigarette smoke stimulated mast cells degranulation (Thomas et al., 1992) while another one showed that mast cells increase fibroblasts-mediated collagen gel retraction (Moyer et al., 2004). No alteration in mast cells degranulation was observed in our study. The higher amount of mast cells in Swiss and C57BL/6 mice strains exposed to cigarette smoke could be explained by an alteration in the initial steps of wound healing process leading to an impairment on recruitment of these cells to the granulation tissue. Surprisingly the amount of mast cells was reduced in BALB/c mice exposed to cigarette smoke, but it should be considered that the amount of mast cells was higher in control BALB/c mice compared to the other strains (80% higher than Swiss and 240% higher than C57BL/6). So we can argue that in BALB/c mast cells did not need to be mobilized, mast cells already present in tissue degranulated and exerted functions, and as mast cells degranulated the amount of mast cells was reduced.

Several studies have shown that cigarette smoke can impair wound healing process through the inhibition of recruitment and migration of fibroblasts (Nakamura et al., 1995); (Wong and Martins-Green, 2004; Wong et al., 2004). The higher amount of myofibroblasts observed in our study 14 days after wounding is a consequence of the impairment in fibroblast recruitment that induced a delay in myofibroblasts differentiation. This delay in myofibroblast differentiation probably is the cause of the delay in wound contraction since myofibroblasts are the main cellular component involved in wound contraction (Serini and Gabbiani, 1999; Wong et al., 2004) showed that cigarette smoke increase fibroblast survival what can lead to development of fibrosis. It is well known that in hypertrophic scars (a typical example of excessive scarring) fibrosis is due to accumulation of myofibroblasts that do not disappear by apoptosis and are continuously secreting extracellular matrix (Desmouliere et al., 1995; Costa et al., 1999; Lorena et al., 2002; Linge et al., 2005). It will be important to evaluate, in future studies, if the delay in cutaneous wound healing induced by cigarette smoke exposition is followed by excessive scarring.

The differences between mice strains and cigarette smoke exposure observed in our study suggest that the genetic predisposition is an important factor that contributes for the use (Collins et al., 1988) and for the effects of tobacco, as well as the velocity and the depth of the inhalation, sex, race and characteristics of the cigarette (Zacny et al., 1987; Bridges et al., 1986). All these aspects in joint could explain differences between individuals to the adverse effects of the cigarette smoke and should be considered in future studies (experimental and in humans).

	Acknowledgments

 
This study was partially supported by CNPq and FAPERJ. BR Souza and JF Cardoso held a graduate fellowship from PIBIC-CNPq and PIBIC-UERJ respectively. TP Amadeu holds a post-graduate fellowship from CAPES.

	References

Top Abstract Introduction Material and Methods Results Discussion References

 
Abraham, SN, & Malaviya, R. (1997). Mast cells in infection and immunity. Infect Immun, 65, 3501-8[Free Full Text]

Bartalesi, B, Cavarra, E, Fineschi, S, Lucattelli, M, Lunghi, B, Martorana, PA, & Lungarella, G. (2005). Different lung responses to cigarette smoke in two strains of mice sensitive to oxidants. Eur Respir J, 25, 15-22[Abstract/Free Full Text]

Bridges, RB, Humble, JW, Turbek, JA, & Rehm, SR. (1986). Smoking history, cigarette yield and smoking behavior as determinants of smoke exposure. Eur J Respir Dis Suppl, 146, 129-37[Medline] [Order article via Infotrieve]

Chow, JY, Ma, L, Zhu, M, & Cho, CH. (1997). The potentiating actions of cigarette smoking on ethanol-induced gastric mucosal damage in rats. Gastroenterology, 113, 1188-97[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

Collins, AC, & Marks, MJ. (1991). Progress towards the development of animal models of smoking-related behaviors. J Addict Dis, 10, 109-26[CrossRef][Medline] [Order article via Infotrieve]

Collins, AC, Miner, LL, & Marks, MJ. (1988). Genetic influences on acute responses to nicotine and nicotine tolerance in the mouse. Pharmacol Biochem Behav, 30, 269-78[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

Costa, AM, Peyrol, S, Porto, LC, Comparin, JP, Foyatier, JL, & Desmouliere, A. (1999). Mechanical forces induce scar remodeling. Study in non-pressure-treated versus pressure-treated hypertrophic scars. Am J Pathol, 155, 1671-9[Abstract/Free Full Text]

Craig, S, & Rees, TD. (1985). The effects of smoking on experimental skin flaps in hamsters. Plast Reconstr Surg, 75, 842-6[Web of Science][Medline] [Order article via Infotrieve]

Desmouliere, A, Redard, M, Darby, I, & Gabbiani, G. (1995). Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. Am J Pathol, 146, 56-66[Abstract]

Ebihara, N, Funaki, T, Murakami, A, Takai, S, & Miyazaki, M. (2005). Mast cell chymase decreases the barrier function and inhibits the migration of corneal epithelial cells. Curr Eye Res, 30, 1061-9[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

Frick, WG, & Seals, RR., Jr. (1994). Smoking and wound healing: a review. Tex Dent J, 111, 21-3[Medline] [Order article via Infotrieve]

Garg, M. (1969). Variation in effects of nicotine in four strains of rats. Psychopharmacologia, 14, 432-8[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

Graves, DT, & Jiang, Y. (1995). Chemokines, a family of chemotactic cytokines. Crit Rev Oral Biol Med, 6, 109-18[Abstract/Free Full Text]

Guerassimov, A, Hoshino, Y, Takubo, Y, Turcotte, A, Yamamoto, M, Ghezzo, H, Triantafillopoulos, A, Whittaker, K, Hoidal, JR, & Cosio, MG. (2004). The development of emphysema in cigarette smoke-exposed mice is strain dependent. Am J Respir Crit Care Med, 170, 974-80[Abstract/Free Full Text]

Hatchell, PC, & Collins, AC. (1977). Influences of genotype and sex on behavioral tolerance to nicotine in mice. Pharmacol Biochem Behav, 6, 25-30[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

Hebert, CA, & Baker, JB. (1993). Interleukin-8: a review. Cancer Invest, 11, 743-50[Web of Science][Medline] [Order article via Infotrieve]

Kenney, EB, Kraal, JH, Saxe, SR, & Jones, J. (1977). The effect of cigarette smoke on human oral polymorphonuclear leukocytes. J Periodontal Res, 12, 227-34[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

Lannan, S, McLean, A, Drost, E, Gillooly, M, Donaldson, K, Lamb, D, & MacNee, W. (1992). Changes in neutrophil morphology and morphometry following exposure to cigarette smoke. Int J Exp Pathol, 73, 183-91[Web of Science][Medline] [Order article via Infotrieve]

Lawrence, WT, Murphy, RC, Robson, MC, & Heggers, JP. (1984). The detrimental effect of cigarette smoking on flap survival: an experimental study in the rat. Br J Plast Surg, 37, 216-9[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

Linge, C, Richardson, J, Vigor, C, Clayton, E, Hardas, B, & Rolfe, K. (2005). Hypertrophic scar cells fail to undergo a form of apoptosis specific to contractile collagen-the role of tissue transglutaminase. J Invest Dermatol, 125, 72-82[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

Lorena, D, Uchio, K, Costa, AM, & Desmouliere, A. (2002). Normal scarring: importance of myofibroblasts. Wound Repair Regen, 10, 86-92[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

Manassa, EH, Hertl, CH, & Olbrisch, RR. (2003). Wound healing problems in smokers and nonsmokers after 132 abdominoplasties. Plast Reconstr Surg, 111, 2082-7. discussion 8–9. discussion 8–9. discussion 8–9.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

Marks, MJ, Burch, JB, & Collins, AC. (1983a). Effects of chronic nicotine infusion on tolerance development and nicotinic receptors. J Pharmacol Exp Ther, 226, 817-25[Free Full Text]

Marks, MJ, Burch, JB, & Collins, AC. (1983b). Genetics of nicotine response in four inbred strains of mice. J Pharmacol Exp Ther, 226, 291-302[Abstract/Free Full Text]

Martin, P. (1997). Wound healing–aiming for perfect skin regeneration. Science, 276, 75-81[Abstract/Free Full Text]

Mio, T, Romberger, DJ, Thompson, AB, Robbins, RA, Heires, A, & Rennard, SI. (1997). Cigarette smoke induces interleukin-8 release from human bronchial epithelial cells. Am J Respir Crit Care Med, 155, 1770-6[Abstract]

Mohammed, AH. (2000). Genetic dissection of nicotine-related behaviour: a review of animal studies. Behav Brain Res, 113, 35-41[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

Mosely, LH, & Finseth, F. (1977). Cigarette smoking: impairment of digital blood flow and wound healing in the hand. Hand, 9, 97-101[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

Moyer, KE, Saggers, GC, & Ehrlich, HP. (2004). Mast cells promote fibroblast populated collagen lattice contraction through gap junction intercellular communication. Wound Repair Regen, 12, 269-75[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

Nakamura, Y, Romberger, DJ, Tate, L, Ertl, RF, Kawamoto, M, Adachi, Y, Mio, T, Sisson, JH, Spurzem, JR, & Rennard, SI. (1995). Cigarette smoke inhibits lung fibroblast proliferation and chemotaxis. Am J Respir Crit Care Med, 151, 1497-503[Abstract]

Reus, WF., 3rd, Colen, LB, & Straker, DJ. (1992). Tobacco smoking and complications in elective microsurgery. Plast Reconstr Surg, 89, 490-4[Web of Science][Medline] [Order article via Infotrieve]

Schwartz, LB, & Austen, KF. (1984). Structure and function of the chemical mediators of mast cells. Prog Allergy, 34, 271-321[Web of Science][Medline] [Order article via Infotrieve]

Serini, G, & Gabbiani, G. (1999). Mechanisms of myofibroblast activity and phenotypic modulation. Exp Cell Res, 250, 273-83[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

Seymour, GJ. (1991). Importance of the host response in the periodontium. J Clin Periodontol, 18, 421-6[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

Silverstein, P. (1992). Smoking and wound healing. Am J Med, 93, 22S-4S[CrossRef][Medline] [Order article via Infotrieve]

Singer, AJ, & Clark, RAF. (1999). Cutaneous wound healing. N Engl J Med, 341, 738-46[Free Full Text]

Smith, JB, & Fenske, NA. (1996). Cutaneous manifestations and consequences of smoking. J Am Acad Dermatol, 34, 717-32. quiz 33–4. quiz 33–4. quiz 33–4.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

Souza, BR, Cardoso, JF, Amadeu, TP, Desmouliere, A, & Costa, AM. (2005). Sympathetic denervation accelerates wound contraction but delays reepithelialization in rats. Wound Repair Regen, 13, 498-505[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

Thomas, PS, Schreck, RE, & Lazarus, SC. (1992). Tobacco smoke releases performed mediators from canine mast cells and modulates prostaglandin production. Am J Physiol, 263, L67-72[Web of Science][Medline] [Order article via Infotrieve]

Tizabi, Y, Mastropaolo, J, Park, CH, Riggs, RL, Powell, D, Rosse, RB, & Deutsch, SI. (1998). Both nicotine and mecamylamine block dizocilpine-induced explosive jumping behavior in mice: psychiatric implications. Psychopharmacology (Berl), 140, 202-5[CrossRef][Medline] [Order article via Infotrieve]

Tomasek, JJ, Gabbiani, G, Hinz, B, Chaponnier, C, & Brown, RA. (2002). Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol, 3, 349-63[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

Valenca, SS, da Hora, K, Castro, P, Moraes, VG, Carvalho, L, & Porto, LC. (2004). Emphysema and metalloelastase expression in mouse lung induced by cigarette smoke. Toxicol Pathol, 32, 351-6[Abstract/Free Full Text]

Wang, H, Ye, Y, Zhu, M, & Cho, C. (2000). Increased interleukin-8 expression by cigarette smoke extract in endothelial cells. Environmental Toxicology and Pharmacology, 9, 19-23[CrossRef][Medline] [Order article via Infotrieve]

Wong, LS, Green, HM, Feugate, JE, Yadav, M, Nothnagel, EA, & Martins-Green, M. (2004). Effects of "second-hand" smoke on structure and function of fibroblasts, cells that are critical for tissue repair and remodeling. BMC Cell Biol, 5, 13[CrossRef][Medline] [Order article via Infotrieve]

Wong, LS, & Martins-Green, M. (2004). Firsthand cigarette smoke alters fibroblast migration and survival: implications for impaired healing. Wound Repair Regen, 12, 471-84[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

Zacny, JP, Stitzer, ML, Brown, FJ, Yingling, JE, & Griffiths, RR. (1987). Human cigarette smoking: effects of puff and inhalation parameters on smoke exposure. J Pharmacol Exp Ther, 240, 554-64[Abstract/Free Full Text]

Toxicologic Pathology, Vol. 35, No. 7, 890-896 (2007)
DOI: 10.1080/01926230701459986


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				J. F. Cardoso, F. A. Mendes, T. P. Amadeu, B. Romana-Souza, S. S. Valenca, L. C. de Moraes Sobrino Porto, J. G. Abreu, and A. Monte-Alto-Costa Ccn2/Ctgf Overexpression Induced by Cigarette Smoke during Cutaneous Wound Healing is Strain Dependent Toxicol Pathol, February 1, 2009; 37(2): 175 - 182. [Abstract] [Full Text] [PDF]

This Article Abstract Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Cardoso, J. F. Articles by Costa, A. M. A. Search for Related Content PubMed PubMed Citation Articles by Cardoso, J. F. Articles by Costa, A. M. A. Social Bookmarking                         What's this?